Department of Clinical Epidemiology University of Santo Tomas Faculty of Medicine and Surgery

1. Department of Clinical Epidemiology University of Santo Tomas Faculty of Medicine and Surgery Case 1: Acute Rheumatic Fever Cueto, Mary Anne to Diaz, Cristina Group 1 – 3B

2. Clinical Decision on a DIAGNOSTIC TEST

3. Case Scenario E.C., a 28 year old housewife was admitted because of dyspnea. Three days ago, she had dental extraction then the next day she began coughing productive of yellowish sputum. She also had chest pain radiating to the back lasting for 30 mins and occurring even at rest. She is febrile (38 C) with joint pain and myalgia. The Past Medical History - frequent streptococcal throat infection in childhood; at age 16 years diagnosed to have valvular heart disease and given monthly Benzathine Penicillin.

4. Salient Features 28 year old housewife Dyspnea History of dental extraction 3 days ago Productive cough Yellowish sputum Unstable angina Febrile Joint pain Myalgia Past medical history of frequent streptococcal throat infection as a child Valvular heart disease

5. Acute Rheumatic Fever and Rheumatic Heart Disease on the Navajo Reservation, 1962-77. JOHN COULEHAN, MD, SHELLIE GRANT, MD, KEITH REISINGER, MD, PAUL KILLIAN, MD, KENNETH D. ROGERS, MD, CHARLES KALTENBACH, DrPH Public Health Reports, January-February 1980, Vol. 95, No. 1

6. Modified Jones Criteria • Presence of two major or one major and two minor, plus evidence of antecedent group A streptococcus infection. Plus evidence of recent streptococcal infection

7. Differential Diagnosis

8. Clinical Question How useful is echocardiography in the evaluation of a 28 year old female presenting with signs and symptoms of acute rheumatic fever?

9. Spectrum of Disease: Rheumatic Fever 65% 75% 25%

10. Search terms: Echocardiography, acute rheumatic fever, adult Population: Population: 452 patients with acute rheumatic fever diagnosed by Jones criteria, 230 males and 222 females, age range from 1 yr 11mos to 51 years old Intervention: Echocardiographic diagnostic procedure outcome: incremental role of echocardiography

12. Journal Title: The Role of Echocardiography in Diagnosing Carditis in the Setting of Acute Rheumatic Fever Ishwarappa B. Vijayalakshmi, Jayapal Mithravinda, Arale N. Prabhu DevaSpectrum of Disease

13. Critical Appraisal RELEVANCE Yes. The aim of the study is to assess the utility of echocardiography in the diagnosis of acute rheumatic fever or its recurrence. We want to know whether we could use echocardiography to diagnose carditis which is a major criterion for the diagnosis of acute rheumatic fever, according to Jones criteria. Carditis is the also the most important prognostic factor in Acute rheumatic fever. Is the object of the study relevant to your clinical question?

14. Validity guides: Yes. The reference standard for the diagnosis of Acute rheumatic fever is through the Jones criteria which was performed in all the subjects. A single cardiologist reevaluated the subjects who was unaware of the diagnosis. Doppler echocardiography was performed by a well trained and experienced echocardiographer, who was unaware of the diagnosis. Was there an independent and blind comparison with a reference standard? What was the reference standard. Were they assessed independently?

15. Did the patient sample include an appropriate spectrum of patients with whom the test will be used? Yes. The patient sample include 492 patients with age range of 1 year old 11 months to 52 years old. 230 males and 222 were females. All were diagnosed with Acute rheumatic fever using the Jones criteria. Was the reference standard done regardless of the result of the diagnostic test being evaluated? Yes. Clinical assessment was done whatever the outcome of the echocardiography was done.

16. Was the method of performing the test described in sufficient detail to permit replication? Yes. Table 1 under the materials and methods described the findings that were assessed using echocardiography. Overall is the study valid? Yes.

17. WHAT ARE THE RESULTS? What were the likelihood ratios for the different possible test results? • Study population:452 • Polyarthritis n=239 • Clinically diagnosed (+): 164 • Clinically diagnosed (-): 75 • Echocardiography (+): 141 • Echocardiography (-): 98 • Polyarthralgia n=213 • Clinically diagnosed (+): 38 • Clinically diagnosed (-): 88 • Echocardiography (+): 125 • Echocardiography (-): 175

18. Will the reproducibility of the test result and its interpretation be satisfactory in my setting? CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS? Yes. Echocardiography can be easily performed in our setting.

19. Are the results applicable to my patient? Will the results change my management? Yes. The population of the study has similar characteristics with our patient. Post test probability if echocardiography is (+): 89% Post test probability if echocardiography is (-): 21% Since the post test probability for both a positive and negative result did not fall within the testing zone, no further diagnostic tools are needed and we can proceed to the treatment

20. Spectrum of disease: Rheumatic Fever 25% 65% 75% Post-test probability if echocardiography is (-): 21% Post-test probability if echocardiography is (+): 81% Post-test probability Lower/upper testing threshold Pretest probability

21. RESOLUTION OF THE CASE SCENARIO Electrocardiography is an accurate diagnostic tool for the diagnosis of carditis in patients with acute rheumatic fever.

22. Treatment • Clinical Question: Can penicillin resolve the symptoms in patients with Streptococcal infection? • Search Terms: streptococcal infection, treatment • Population: 15-60 y/o males and females with sore throat • Intervention: Penicillin V • Comparison: Placebo • Outcome: Resolution of symptoms in the first week, eradication of bacteria after two weeks, and recurrences of sore throat after two, four, and six months.

24. Penicillin for acute sore throat: randomised double blindtrial of seven days versus three days treatment or placeboin adultsSjoerd Zwart, Alfred P E Sachs, Gijs J H M Ruijs, Jan W Gubbels, Arno W Hoes, Ruut A de MelkerBMJ 2000;320:150–4 • Validity Guides • Was the assignment of patients to treatment randomized? Was randomization concealed? • Yes. Patients were randomly assigned to one of three treatment groups: penicillin V for seven days, penicillin V for three days followed by placebo for four days, or placebo for seven days. The dosage was two 250 mg capsules three times daily. Paracetamol tablets were supplied to all patients to be used on demand. (Participants and Methods, Treatment Groups, p. 151) • Was the follow up sufficiently long and complete? • Yes. Fourteen days after inclusion the patients were re­examined by their general practitioner. After two, four, and six months the patients were interviewed by telephone on recurrent sore throat and other complaints of the respiratory tract.(Participants and Methods, Clinical Follow-up, p. 151)

25. Was the data analyzed on an intention-to-treat basis? • Yes. All analyses were carried out with spss version 7.0, using an intention to treat approach. (Participants and Methods, Data Analysis, p. 151) • Was there adequate blinding of subjects and researchers? • Randomised double blind placebo controlled trial. (Abstract, Design, p. 150) • Were there similar baseline characteristics in each group? • Yes. Refer to table 1. • Groups treated equally other than intervention? • Yes.

26. Clinical Importance • What is the magnitude of treatment effect? • Endpoint: Sore throat (duration)   There is a -32% relative risk reduction in the end point sore throat using the 7-day penicillin V treatment. The relative risk (EER/CER) for penicillin is 132%. And we need to harm 4 (NNT= -4) patients to prevent shortening of sore throat duration. • Endpoint: bacterial eradication • There is a -929% relative risk reduction of bacterial eradication using the 7-day penicillin V treatment. The relative risk (EER/CER) for penicillin is 1028.6%. And we need to harm 2 (NNT= -2) patients to prevent bacterial eradication. • Endpoint: Sore throat (recurrence) • There is a -75% relative risk reduction in the recurrence of sore throat using the 7-day penicillin V treatment. The relative risk (EER/CER) for penicillin is 175%. And we need to harm 17 (NNT= -17) patients to prevent recurrence of sore throat.

28. Relevance • Is the objective of the article comparing therapeutic interventions similar to your clinical dilemma? • Yes, one of the initial steps in the management of acute rheumatic fever is to eradicate the infecting agent (Group A Beta Hemolytic Streptococci). • External Validity • Are The Results of the Study Applicable to the Patient? • Yes. The patient is included within the age range of the study subjects. Both male and female subjects were used in the study. The patient also has history of recurrent streptococcal throat infections since childhood. • Were All Clinically Important Outcomes Considered? • Yes, resolution of symptoms, bacteriological response and recurrences and adverse effects. (Results, p. 152)

29. Is treatment feasible? • Yes. Penicillin V is readily available and the response to the treatment is easily monitored. • Patient preferences • The patient may be informed of the different interventions and allowed to choose what she prefers. • Benefit vs. harm • According to the study’s results, there is a 24% reduction in duration of sore throat, 65% difference in eradication of bacteria and 6% difference in incidence of recurrence of sore throat in patients treated with penicillin compared to placebo. 

30. Resolution • The bottom line of this clinical study is that a 7-day course of penicillin is effective in resolving the symptoms in patients with Streptococcal infection of the throat.

31. CRITICAL APPRAISAL OF ARTICLE ON HARM

32. Discontinuing Rheumatic Fever Prophylaxis in Selected Adolescents and Young Adults: A Prospective Study Ximena Berrios, MD; Emilo del Campo, MD; Beatriz Guzman, RN; and Alan L. Bisno, MD Search terms: penicillin, rheumatic fever, safety, discontinuance

33. Relevance • Yes. The investigator only included patients ranging in age at study entry from 15 to 44 years (mean, 24.5 years). Patients were entered in the Control and Prevention Program because of an attack of acute rheumatic fever (observed and documented by the Program physicians) that fulfilled the modified Jones criteria or because they were referred from ambulatory clinics with rheumatic valvular heart disease. The latter was confirmed by Program cardiologists who did clinical examinations as well as reviewed electrocardiograms and chest roentgenograms. • (page 3, Methods: Patients, 2nd paragraph) Were there clearly identified comparison groups? Validity

34. Validity

38. Results What is the magnitude of the association between exposure and outcome?Was the estimate of the risk precise? • Among 59 patients, 48 had completed their period of prophylaxis • There were two recurrences of rheumatic fever during the 3346 patient-months (278.8 patient-years) of follow-up • Recurrence rate: 0.72 (CI, 0.2 to 2.6) per 100 patient-years of prospective surveillance. • Ninety-five percent confidence intervals were determined using the Poisson probability function generator (SAS version 6.03, SAS Institute Inc., 1988). (page 5, Results & page 4, Statistical Analysis)

39. Are the study patients similar to my own? Clinical Applicability • Yes. (page 1, Abstract: Patients & page 3, Methods: Patients) Is our patient so different from those in the study that its results cannot apply? • No, our patient is the same with the patients included in the study. Therefore, this study can be applied to our patient. What is our patient’s risk of benefit and harm from the exposure? • prone to develop recurrent attacks if they have immunologically significant group A streptococcal throat infections • antibacterial prophylaxis with penicillin has an over-all benefit • possibility of recurrence despite completion of therapy affected by exposure to the pathogens, reliability in reporting promptly to the physician any episodes of pharyngitis, and the incidence of rheumatic fever in the community. • risk for development of or exacerbation of rheumatic heart disease and carditis (page 2, Conclusion & page 8, Discussion)

40. Resolution to the Scenario What alternative treatments are available? There was no mention in the article of alternative medications. Based on the appraisal, the patient will be advised that prophylactic treatment of Penicillin for her acute rheumatic fever may be discontinued after 5 years given that there was no carditis during the attack. Otherwise, it will have to take 10 years. Individuals who have reached their early twenties, had their most recent attack more than 5 years ago, and are free of rheumatic heart disease can be taken off prophylaxis with relative safety.

41. PROGNOSIS

42. CLINICAL QUESTON: What is the long term prognosis of rheumatic fever patients receiving regular benzathine penicillin? Population: Rheumatic fever patients Intervention: Prophylaxis with benzathine penicillin Outcome:Valvular heart disease, Recurrence of rheumatic fever Bacterial endocarditis, Death Methods: Cohort SEARCH TERMS: Rheumatic fever , prophylaxis, long term prognosis

43. Long-Term Prognosis of Rheumatic Fever Patients Receiving Regular Intramuscular Benzathine Penicillin. Tompkins D, Boxerbaum B, Liebman J., Circulation Journal of the American Heart Association 45;543-551, 1972

44. Critical Appraisal

45. Critical Appraisal

46. How large is the likelihood of outcome to occur in those with the prognostic factor in a specified period of time? Was it statistically significant?

47. Can the results help me in caring for my patients?

48. Resolution of the problem in the scenario Based on the Thompson et al. study, our group advices that the patient in the case scenario continue with her intake of benzathine penicillin monthly even if she had an incident on rheumatic fever while taking it because further valvular damage, bacterial endocarditis, higher risk for recurrence of rheumatic fever and even death would occur without it.